It is well established that genetic predisposition plays a major role in the susceptibility of individuals to systemic lupus erythematosus (SLE). Therefore, definition of the causal mechanisms responsible for this disease will require knowledge of both the genetic alterations and the nature of their contribution to autoimmunity. We have previously identified in (NZBxNZW)F2 mice eight loci designated Lbw1-8 on chromosomes 17, 4, 5, 6, 7, 18, 1 and 11, respectively, that were linked to one or more SLE disease traits. Interval-specific congenic strains for Lbw2, Lbw5, and Lbw7 have been generated and the specific component phenotypes have been identified for Lbw2 and Lbw5. Further mapping, using congenic mice with smaller Lbw regions, indicated that Lbw2 and Lbw5 loci are both composed of more than one susceptibility locus, and have localized four QTL traits to 3-9 cM-size intervals. These studies clearly demonstrate the feasibility of this approach for narrowing Lbw QTL intervals relevant to SLE and have generated the materials necessary for the identification of the predisposing genes. This proposal will perform a second round of mapping that will localize two Lbw2 subloci, Lbw2b and Lbw2e, responsible for autoimmune hemolytic anemia and mortality, respectively, to <1 Mb-sized intervals. The specific lupus-related phenotypes will be defined for these subloci and the narrowed intervals will be analyzed for the Lbw susceptibility genes. Identification of the susceptibility genes and elucidation of their roles in the induction of lupus should provide significant insights into the etiopathogenesis of genetically-determined autoimmune diseases.